rs397516824
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4BP6_Very_StrongBS2
The NM_002880.4(RAF1):c.66T>G(p.Phe22Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,614,116 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F22C) has been classified as Uncertain significance.
Frequency
Consequence
NM_002880.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAF1 | NM_002880.4 | c.66T>G | p.Phe22Leu | missense_variant | 2/17 | ENST00000251849.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAF1 | ENST00000251849.9 | c.66T>G | p.Phe22Leu | missense_variant | 2/17 | 1 | NM_002880.4 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152222Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251480Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135912
GnomAD4 exome AF: 0.000131 AC: 191AN: 1461894Hom.: 1 Cov.: 32 AF XY: 0.000132 AC XY: 96AN XY: 727248
GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152222Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74372
ClinVar
Submissions by phenotype
RASopathy Uncertain:1Benign:1
Likely benign, reviewed by expert panel | curation | ClinGen RASopathy Variant Curation Expert Panel | Apr 03, 2017 | The c.66T>G (p.Phe22Leu) variant has been identified in patients with clinical features of a RASopathy, however the variant did not segregate with disease in affected family members (BS4; GeneDx, Partners LMM, Invitae internal data GTR ID's: 26957, 21766, 500031; ClinVar SCV000218672.4; SCV000061358.5). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; LMM internal data; SCV000061358.5). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS4, BP5. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 04, 2023 | This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 22 of the RAF1 protein (p.Phe22Leu). This variant is present in population databases (rs397516824, gnomAD 0.01%). This missense change has been observed in individual(s) with Noonan syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 40583). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RAF1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 10, 2016 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 29, 2023 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
RAF1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 20, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at